Pharmaceutically useful 2,5-dioxo-1H-octahydroimidazo[1,2-A]azepines

ABSTRACT

Imidazole derivatives are described which are useful in restoring learning and treating memory difficulties. A compound of the invention is 2,5-dioxohexahydro-1H-pyrrolo[1,2-a]imidazole.

This is a division of application Ser. No. 07/669,806 filed Mar. 15,1991 now U.S. Pat. No. 5,130,319 which is a division of application Ser.No. 07/307,012 filed Feb. 6, 1989 now U.S. Pat. No. 5,053,422.

The present invention relates to novel compounds, processes for theirpreparation, pharmaceutical compositions containing them and their usein therapy, in particular as nootropic agents.

Compounds having nootropic activity are known in the art. In particular,4-substituted derivatives of 2-oxo-1-pyrrolidineacetamide are valuedpsychotropic agents that restore cognitive function that has beendamaged as a result of various pathologies. These drugs are describedfor example in Pharm. Res. Commun., 16, 67, (1984) by Banfi et al and inDrug Development Res.; 2, 447 (1982) by Itil et al. A particularly wellknown member of the above-noted class is 4-hydroxy-2-oxo-1-pyrrolidineacetamide (oxiracetam).

It has now been found that certain perhydroazacycloalka[1,2-a]imidazolederivatives also demonstrate psychotropic properties and are expected tobe of use as nootropic agents.

The present invention therefore provides, in a first aspect, compoundsof structure (1) ##STR1## in which,

R¹ is hydrogen, C₁₋₄ alkyl, CHR⁶ CONHR⁷ or CHR⁶ COOR⁷ in which R⁶ and R⁷are each hydrogen or C₁₋₄ alkyl;

R² is hydrogen, C₁₋₅ alkyl or any residue R² of an amino acid R²CH(NH₂)COOH

R³ is hydrogen, C₁₋₄ alkyl, CONH₂ or CO₂ R⁸ in which R⁸ is hydrogen orC₁₋₄ alkyl; and

n is 2, 3 or 4.

Suitably R¹ and R³ are each C₁₋₄ alkyl and R² is C₁₋₅ alkyl. Moresuitably two of R¹ to R³ are hydrogen and the third is other thanhydrogen. Preferably R¹ to R³ are each hydrogen. Preferably n is 2.Suitable groups R² which are any residue R² of a amino acid R²CH(NH₂)CO₂ H, include for example CH₃, (CH₃)₂ CH, PhCH₂, CH₂ OH, CH₂ CH₂CONH₂ and CH₂ COOH.

C₁₋₄ and C₁₋₅ alkyl groups can be straight or branched, in particularmethyl, ethyl or isobutyl.

Particular compounds of the present invention include, for example,

2,5-dioxohexahydro-1H-pyrrolo[1,2-a]imidazole;

2,5-dioxo-7a-methylhexahydro-1H-pyrrolo[1,2-a]imidazole;

2,5-dioxo-3-methylhexahydro-1H-pyrrolo[1,2-a]imidazole;

2,5-dioxo-3-isobutylhexahydro-1H-pyrrolo[1,2-a]imidazole;

2,5-dioxo-1-ethylhexahydro-1H-pyrrolo[1,2-a]imidazole;

2,5-dioxo-3,7a-dimethylhexahydro-1H-pyrrolo[1,2-a]imidazole;

ethyl 2,5-dioxohexadro-1H-pyrrolo[1,2-a]imidazole-1-acetate;

2,5-dioxohexadro-1H-pyrrolo[1,2-a]imidazole-1-acetamide;

(3-L)-3-benzyl-2,5-dioxhexahydro-1H-pyrrolo[1,2-a]imidazole;

(3-L)-3-hydroxymethyl-2,5-dioxohexahydro-1H-pyrrolo [1,2-a]imidazole;

2,5-dioxohexahydro-1H-pyrrolo[1,2-a]imidazole-7a-carboxylic acid;

ethyl 2,5-dioxohexahydro-1H-pyrrolo[1,2-a]imidazole-7a-carboxylate;

2,5-dioxohexahydro-1H-pyrrolo[1,2-a]imidazole-7a-carboxamide;

2,5-dioxooctahydro-1H-imidazo[1,2-a]pyridine;

2,5-dioxooctahydro-1H-imidazo[1,2-a]azepine.

It will be appreciated that certain of the compounds of structure (I)can contain one or more chiral centres. The present invention covers alloptical isomers of these compounds in their fully and partially resolvedforms and in the form of racemic mixtures.

The present invention therefore provides in a further aspect, a processfor the preparation of compounds of structure (1) which comprises:

a) reaction of a compound of structure (2) with a compound of structure(3): ##STR2## in which R¹ to R³ and n are as described for structure(1), R⁴ is hydrogen and R⁵ is hydrogen, C₁₋₄ alkyl or benzyl; or

b) cyclization of a compound of structure (4) ##STR3## in which R¹ to R³and n are as described for structure (1), R⁴ is hydrogen and R⁵ ishydrogen, C₁₋₄ alkyl or benzyl.

Suitably the reaction between compounds of structure (2) and (3) iscarried out by heating in a suitable solvent and in the presence of abase, such as an alkali metal alkoxide, when compound (2) is employed inthe form of an acid addition salt (e.g. hydrochloride). Preferably thereaction is carried out at reflux in water as a solvent.

Suitably, the cyclization of a compound of structure (4) when R⁴ ishydrogen and R⁵ is alkyl or benzyl is carried out by heating thecompound, optionally under reduced pressure, in the presence or absenceof solvent. Preferably, the cyclization is effected by heating thecompound of structure (4) in water at reflux temperature. When R⁵ ishydrogen, cyclization will require activation of the carboxyl group orthe use of a peptide coupling reagent in a dipolar aprotic solvent.

Suitable methods for activating carboxyl groups and suitable peptidecoupling reagents are all well known to the art and are described forexample in "Peptide Synthesis" by M. Bodansky, Y. Klausner and M.Ondetti (Wiley 1976) and in "Protective Groups in Organic Synthesis" byT. W. Greene (Wiley, 1981). Examples of activated derivatives ofcarboxyl groups are acyl chlorides, acyl azides, mixed anhydrides (e.g.formed with an alkyl chloroformate or pivaloyl chloride) and activatedesters (e.g. trichlorophenyl, N-hydroxysuccinimido and1-hydroxybenzotriazole esters). Examples of peptide coupling reagentsare carbodiimides and Woodward's Reagent K(N-ethyl-5-phenylisoxazolium-3'-sulphonate).

Suitable dipolar aprotic solvents are tetrahydrofuran, acetonitrile,dimethylformamide or dimethylsulfoxide.

Preferably the cyclization of a compound of structure (4) in which R⁴ ishydrogen and R⁵ is C₁₋₄ alkyl or benzyl is carried out in a suitablesolvent, such as methanol, in the presence of ammonium hydroxide atmoderate temperatures of about 50° C. and for short reaction times ofabout 1 hour, or until reaction is complete. Such cyclization producesthe compounds of structure (I) in high yields, is novel, and forms afurther aspect of the invention.

The starting compounds (2), (3) and (4) can be prepared by methods knownto those skilled in the art or analogous to those known in the art; forexample, compounds of structure (2) in which R¹ and R⁴ are hydrogen andR² is methyl or isobutyl can be prepared by procedures described in J.Am. Chem. Soc., 53, 3183 [1931] and 79, 4686, [1957]; compounds ofstructure (2) in which R¹ and R⁴ are hydrogen and R² is CH₂ OH can beprepared by procedures described in J. Biol. Chem., 212, 271 [1955];compounds of structure (2) in which R¹ is ethyl and R² and R⁴ arehydrogen can be prepared by the method described in Chem. Ber., 89,1363, [1956]; for example compounds of structure (3) in which R³ ismethyl, R⁵ is ethyl and n is 2 can be prepared by the proceduredescribed in J. Prakt. Chem. 1 (4), 153 [1955]; compounds of structure(3) in which R³ is hydrogen, R⁵ is ethyl and n is 2 can be prepared bythe procedure described in J. Pharm. Soc. Japan, 75, 622 [1955];compounds of structure (3) in which R³ is hydrogen, R⁵ is methyl and nis 3 can be prepared by the procedure described in Synthesis, 1982, 881;compounds of structure (3) in which R³ is hydrogen, R⁵ is methyl and nis 4 can be prepared by the procedure described in J. Org. Chem., 53,1064 [1988].

Compounds of structure (3) in which R³ is hydrogen R⁵ is isobutyl and nis 2 can be prepared by reduction of a compound of structure HCOCH═CHCO₂iBu. This process is new and forms a further aspect of the presentinvention. Suitably the reaction is carried out in a C₁₋₄ alkanol, inthe presence of a noble metal catalyst at atmospheric pressure;preferably the reaction is carried out in 96% ethanol in the presence ofa 5% palladium on charcoal catalyst.

Compounds of the structure (4) in which R⁴ is hydrogen can be preparedby hydrogenation of compounds of structure (5) ##STR4## in which R¹ toR³ are as described for structure (1) m is 0, 1 or 2 and R⁵ is hydrogenor C₁₋₄ alkyl or benzyl; or directly from the appropriate compounds ofstructure (2) in which R⁴ is hydrogen and (3). Alternatively, compoundsof structure (4) in which R⁴ is hydrogen can be obtained by catalytichydrogenation of compounds of structure (4) in which R⁴ is benzyl,which, in turn, can be prepared from the appropriate compounds ofstructure (2), in which R⁴ is benzyl, and (3). Suitably thehydrogenations are carried out under conditions which remove theN-protecting groups and also reduce the side-chain double bond, whenpresent, for example by using a noble metal catalyst, such as palladiumon charcoal in a suitable solvent, such as ethanol. When R⁵ is benzyl,compound (4) in which R⁵ is hydrogen is directly obtained.

Compounds of structure (5) can themselves be prepared by reactionbetween compound of structure (2) in which R⁴ is PhCH₂ OCO and anappropriate carbonyl compound of structure (6)

    R.sup.3 COCH═CH(CH.sub.2).sub.m CO.sub.2 R.sup.5       ( 6)

in which R³, R⁵ and m are as hereinbefore described.

The reaction is carried out in a suitable solvent at elevatedtemperature, optionally in the presence of a suitable catalyst.Preferably the reaction is carried out in toluene at elevatedtemperature, in the presence of p-toluenesulphonic acid monohydrate asdescribed in, Tetrahedron, 41, 611, 1985.

The starting compounds (2) in which R⁴ is PhCH₂ or PhCH₂ OCO and (6) canbe prepared by methods known to those skilled in the art or analogous tothose known in the art; for example compounds of structure (2) in whichR¹ and R² are hydrogen and R⁴ is PhCH₂ OCO can be prepared by proceduresdescribed in J. Am. Chem. Soc., 73, 2936 [1951], compounds of structure(2) in which R¹ and R² are hydrogen and R⁴ is benzyl can be prepared byprocedures described in Synthesis, 1983, 329; and, for example,compounds of structure (6) in which R³ is hydrogen, R⁵ is ethyl and m is2 can be prepared by procedures described in J. Pharm. Soc. Japan, 75,622 [1955]; compounds of structure (6) in which R³ is methyl, R⁵ ismethyl and m is 0 can be prepared by the procedure described in J. Am.Chem. Soc., 68, 2510 [1946]; compounds of structure (6) in which R³ ismethyl, R⁵ is ethyl and m is 0 can be prepared by procedures describedin Annalen der Chemie, 264, 248 [1891]. In particular compound (6) inwhich R³ is hydrogen, R⁵ is isobutyl and m is 0 can be prepared by basecatalyzed rearrangement of isobutyl 3,4-epoxybutanoate (whosepreparation is described in E.P. Appl. 154,490) and subsequent oxidationwith methods known to those skilled in the art or analogous to thoseknown in the art; for example with a transition metal compound asdescribed in "Oxidation" Vol. 1, by D. G. Lee; R. L. Augustine Ed.,(Dekker 1969).

The compounds of structure (1) are of use as therapeutic agents and inparticular have nootropic activity, that is to say they help restorelearning and memory difficulties associated with ageing and variouspathologies including for example Alzheimer's disease.

The present invention therefore provides, in a further aspect a methodof restoring learning and treating memory difficulties which comprisesadministering to a mammal in need thereof a non-toxic effective amountof a compound of structure (1). The cognitive disorders occurring insuch pathologies are known to be related to deficits in the braincholinergic system as shown both by morphological (B. E. Tomlinson in"Biochemistry of Dementias"; P. J. Roberts Ed.; John Wiley & Sons, NewYork, N.Y. p. 15-22, 1980) and neurochemical findings (R. T. Bartus etal., Science, 217, 408, 1982). It is also well known that significantimpairments of cognitive functions are the more evident and debilitatingsymptoms observed in patients with Alzheimer's disease, senile dementiaof the Alzheimer type and multiinfarctual dementia. On the other hand,the anticholinergic drug scopolamine, produces in humans (D. A.Drachman, Archs. Neurol., Chicago, 30, 113, 1974) as well as in animals(D. A. Eckerman, Pharmacol. Biochem. Behav., 12, 595, 1980) asignificant memory loss, which is directly related to a decrease ofacetylcholine concentration in specific cerebral areas such as thecerebral cortex and the hippocampus. On the basis of these premises,compounds of structure 1 have been specifically tested in rats againstboth the disruptive action of scopolamine on mnestic trace and on thereduction of acetylcholine levels in hippocampus. To evaluate the effecton memory and learning, one trial-step through-passive avoidance test inmale Wistar rats (150-160 g) was used. The equipment was essentially thesame described by Essman (Pharmacol. Res. Commun., 5, 295, 1973).

The passage from a light box into a dark one was punished by unavoidableelectric foot shocks. The animals must learn to avoid, after a singlelearning session, the crossing from the light to the dark box. Thirtyminutes after the first session (learning session), the learning effectwas quantified (retest session) by means of the latencies (in seconds)between the admission of animals into the light box and the enteringinto the dark one. The learning effect is substantially impaired by atreatment with scopolamine (0.63 mg/kg s.c.) sixty minutes before thelearning session. Saline or the test compounds were administered i.p.thirty minutes before scopolamine. The control group was treated in thesame way but with saline only. For example, results on compounds A (1,R¹ =R² =R³ =H and n=2), B (1, R¹ =R² =H, R³ =Me and n=2) and (1, R¹, =H,R² =R³ =Me, n=2 and the configuration at carbon in 3 position is S) incomparison with oxiracetam are given in Table 1.

                  TABLE 1                                                         ______________________________________                                        One-trial step through passive avoidance test in rats:                        activity of compound A and oxiracetam against amnesia                         induced by scopolamine (0.63 mg/kg s.c.)                                                        Latencies                                                                   Dose    Learn-                                                                mg/kg   ing     Retest                                                                              Dif-                                    Treatment.sup.a i.p.    session session                                                                             ference.sup.b                           ______________________________________                                        SALINE          --      21.3    118.3  97.0**                                 SCOPOLAMINE     --      20.3    72.5   52.2                                   A + SCOPOLAMINE 0.1     20.9    100.5  79.6*                                  A + SCOPOLAMINE 0.3     19.7    103.6  83.9*                                  A + SCOPOLAMINE 1       19.7    120.0 100.3**                                 B + SCOPOLAMINE 0.1     20.4    98.4   78.0*                                  B + SCOPOLAMINE 0.3     18.6    102.3  83.7*                                  B + SCOPOLAMINE 1       21.1    119.0  97.9**                                 C + SCOPOLAMINE 0.1     20.3    96.4   76.1*                                  C + SCOPOLAMINE 0.3     21.3    107.5  86.2*                                  C + SCOPOLAMINE 1       19.5    120.0 100.5**                                 OXIRACETAM + SCOP.                                                                            3       21.5    78.0   56.5 n.s.                              OXIRACETAM + SCOP.                                                                            10      19.7    115.0  95.3**                                 OXIRACETAM + SCOP.                                                                            30      19.1    120.0 100.9**                                 ______________________________________                                         .sup.a Twenty rats were used for each experimental group                      .sup.b cutoff time =  120 sec.                                                *Dunnett's test less than 0.05 versus scopolamine                             **Dunnett's test less than 0.01 versus scopolamine                       

When used in the therapeutic treatment of humans and animals, thecompounds of structure (1) are normally formulated in accordance withstandard pharmaceutical practice as a pharmaceutical composition.Therefore in another aspect the present invention there is provided apharmaceutical composition which comprises a compound of structure (1)or a pharmaceutically acceptable salt thereof and a pharmaceuticallyacceptable carrier.

The compounds of the structure (1) may be administered in standardmanner for the treatment of the indicated diseases, for example orally,parenterally, rectally, transdermally or by transmucosal (for examplesub-lingual, or buccal or insufflatory) administration.

The compounds of the structure (1) which are active when given orally orvia sub-lingual or buccal administration can be formulated as syrups,tablets, capsules and lozenges. A syrup formulation will generallyconsist of a suspension or solution of the compound or salt in a liquidcarrier for example, ethanol, glycerine or water with a flavouring orcolouring agent. Where the composition is in the form of a tablet, anypharmaceutical carrier routinely used for preparing solid formulationsmay be used. Examples of such carriers include magnesium stearate,starch, lactose and sucrose. Where the composition is in the form of acapsule, any routine encapsulation is suitable, for example using theaforementioned carriers in a hard gelatin capsule shell. Where thecomposition is in the form of a soft gelatin shell capsule anypharmaceutical carrier routinely used for preparing dispersions orsuspensions may be utilised, for example aqueous gums, celluloses,silicates or oils and are incorporated in a soft gelatin capsule shell.

Typical parenteral compositions consist of a solution or suspension ofthe compound of the structure (1) in a sterile aqueous or non-aqueouscarrier optionally containing a parenterally acceptable oil, for examplepolyethylene glycol, polyvinylpyrrolidone, lecithin, arachis oil, orsesame oil.

A typical suppository formulation comprises a compound of structure (1)which is active when administered in this way, with a binding and/orlubricating agent, for example polymeric glycols, gelatins, cocoa-butteror other low melting vegetable waxes or fats.

Typical transdermal formulations comprise a conventional aqueous ornon-aqueous vehicle, for example a cream, ointment, lotion or paste orcan be in the form of a medicated plaster, patch or membrane.

Preferably the composition is in unit dosage form, for example a tabletor capsule, so that the patient may administer to himself a single dose.

Oxiracetam is a compound which is used in the treatment of seniledementia and related disease conditions. The compounds of structure (1)can be administered in similar regimes to those established foroxiracetam with any appropriate adjustment in dose levels or frequencyof dosing having regard to the greater activity and betterpharmacological profile of the compounds of structure (1).

Each dosage unit for oral administration contains suitably from 0.05mg/Kg to 20 mg/Kg, and preferably from 0.1 mg/Kg to 5 mg/Kg, and eachdosage unit for parenteral administration contains suitably from 0.05mg/Kg to 10 mg/Kg, of a compound of structure (1).

The daily dosage regimen for oral administration is suitably about 0.05mg/Kg to 50 mg/Kg, more suitably about 0.1 mg/Kg to 20 mg/Kg of acompound of structure (1). The active ingredient may be administeredfrom 1 to 6 times daily. The compounds of structure (1) may beco-administered with other pharmaceutically active compounds, forexample in combination, concurrently or sequentially, particularly withother compounds used in the treatment of elderly patients e.g.tranquillisers, diuretics, antihypertensives, vasodilators and inotropicagents.

The invention is illustrated by the following Examples.

Preparation 1 A) Isobutyl (E)-4-hydroxy-2-butenoate

To an ice cold solution of isobutyl 3,4-epoxybutanoate (300 g, 1.9 mol)in toluene (2.5 l), sodium hydride (55% suspension in oil, 3 g, 0.07mol) was added portionwise. The solution was stirred at 0°-5° C. for 1hour, then 55% sodium hydride (3 g, 0.07 mol) was added again. Afterstirring at room temperature for 1 hour the solution was washed withbrine (0.4 l) containing 10% hydrochloric acid (60 ml), then twice withbrine (300 ml each). The organic solution was dried over anhydroussodium sulfate and evaporated to dryness. Distillation of the residueafforded 175 g (58.3%) of the title compound as a colourless oil, b.p.89°-90° C. (0.5 mmHg). NMR (CDCl₃): delta_(H) =7.05 (dt, J=15 and 4 Hz,1H, CH═CH--CO), 6.12 (dt, J=15 and 2 Hz, 1H, CH═CH--CO), 4.40 (c.a, 2H,CH₂ OH). MS (E.I., 70 eV, 1.5 mA) m/z=127 (M-CH₂ OH)⁺, 85 (M-C₃ H₅ O₂)⁺.

B) Isobutyl (E)-4-oxo-2-butenoate

To a suspension of pyridinium chlorochromate (100 g, 0.463 mol) indichloromethane (350 ml), a solution of isobutyl (E)-4-hydroxycrotonate(50 g, 0.316 mol) in dichloromethane (150 ml) was added. The internaltemperature gradually rose to 40° C. and stirring was continued for 2hours without cooling. Diethyl ether (0.9 l) was added and thesupernatant was decanted from the black gum. The insoluble residue waswashed twice with 300 ml portions of diethyl ether. The combined organicsolutions were passed through a short pad of Florisil and the solventwas removed by distillation, to yield 45.3 g (91.6%) of the titlecompound, as a pale yellow oil, Rf=0.5 (silica gel plates,cyclohexane-ethyl acetate 6:4). NMR (CDCl₃): delta_(H) =9.80 (ABX, 1H,CHO), 6.98 and 6.75 (ABX, J_(AB) =15 Hz, 2H, CH═CH). MS (E.I., 70 eV,1.5 mA) m/z=155 (M-H)⁺, 85 (M-C₃ H₃ O₂)⁺.

C) Isobutyl 4-oxobutanoate

To a solution of isobutyl (E)-4-oxo-2-butenoate (97 g, 0.62 mol) in 96%ethanol (800 ml), 5% palladium on charcoal (9.7 g) was added andhydrogen was bubbled at 5°-10° C. and at atmospheric pressure for 20hours. Removal of the catalyst and evaporation of the solvent gave 97.6g (99%) of the title compound; Rf=0.41 (silica gel plates, eluent:cyclohexane-ethyl acetate 6:4). NMR (CDCl₃): delta_(H) =12.5 (d, J=1 Hz,1H, CHO); 3.85 (d, J=6 Hz, 2H, COOCH₂); 2.80-2.40 (c.a., 4H, CH₂ CH₂CO); 2.10-1.70 (c.a., 1H, CH₂ CHMe₂); 0.90 (d, J=6 Hz, 6H, CH₃). MS(E.I., 70 eV, 1.5 mA) m/z=103 (M-C₃ H₃ O)⁺, 85 (M-C₃ H₅ O₂)⁺, 57 (M-C₄H₅ O₃)⁺.

EXAMPLE 1 A) Isobutyl(E)-1-benzyloxycarbonyl-4-oxo-2-imidazolidineacrylate

To a solution of isobutyl (E)-4-oxo-2-butenoate (11 g, 70.43 mmol) intoluene (170 ml) benzyloxycarbonylglycinamide (14.67 g, 70.43 mmol) andp-toluensulfonic acid monohydrate (0.67 g, 3.5 mmol) were added. Themixture was refluxed for 4 hours in a Dean-Stark apparatus. The obtainedsolution was cooled, the precipitate matter was filtered off and thefiltrate was washed with a saturated solution of sodium hydrogencarbonate (50 ml) and brine (50 ml). The organic phase, dried overanhydrous sodium sulfate, was evaporated to dryness. The residue waschromatographed over silica gel (ethyl acetate-cyclohexane 1:1). Thecollected fractions were evaporated and the residue, triturated withdiisopropyl ether, afforded 7.72 g (31.6%) of the title compound as awhite solid, m.p. 97°-100° C. NMR (CDCl₃): delta_(H) =6.80 (ABX, J_(AB)=15 Hz, J_(AX) =7 Hz, 1H, CH═CH--CO), 6.15 (c.a., 1H, CH═CH--CO), 5.70(ABX , J_(AB) =7 Hz, CH═CH--CH), 4.10 and 3.97 (ABq, J=16 Hz, 2H, COCH₂N). MS (E.I., 70 eV, 1.5 mA) m/z=346 (M⁺), 239 (M-C₇ H₇ O)⁺, 91 (C₇ H₇⁺).

B) Isobutyl 4-oxo-2-imidazolidinepropanoate

To a solution of isobutyl(E)-1-benzyloxycarbonyl-4-oxo-2-imidazolidineacrylate (7.7 g, 22.2 mmol)in 96% ethanol (200 ml), 5% palladium on charcoal (0.5 g) was added andhydrogen was bubbled at 20° C. and at atmospheric pressure for 2 hours.Removal of the catalyst and evaporation of the solvent gave a residuewhich was triturated with diisopropyl ether to give 4.1 g (86%) of thetitle compound, m.p. 50°-52° C. NMR (CDCl₃): delta_(H) =4.45 (t, J=6 Hz,1H, N--CH--N), 3.10 (s, 2 H, N--CH₂ --CO). MS (E.I., 70 eV, 1.5 mA)m/z=214 (M⁺), 157 (M-C₄ H₉)⁺, 85 (M-C₇ H₁₃ O₂)⁺.

C) 2,5-Dioxohexahydro-1H-pyrrolo[1,2-a1imidazole

Isobutyl 4-oxo-2 imidazolidinepropanoate (4 g, 18.7 mmol) was stirred at120°-130° C. (external temperature) under vacuum for 3-5 hours. Theresidue was triturated with ethyl acetate to yield 0.75 g (28.6%) of thetitle compound, m.p. 155°-157° C. NMR (CDCl₃): delta_(H) =5.45 (t, J=6Hz, 1H, CH), 4.23 and 3.60 (ABq, J=16 Hz 2H, COCH₂ N). MS (E.I., 70 eV,1.5 mA) m/z=140 (M⁺), 97 (M-CONH)⁺.

EXAMPLE 2 2,5-Dioxo-7a-methylhexahydro-1H-pyrrolo[1.2-a]imidazole

To a solution of glycinamide hydrochloride (18.4 g, 0.166 mol) in water(200 ml), adjusted to pH 9.5 with 10% sodium hydroxide (about 60 ml),ethyl 4-oxopentanoate (20 g, 0.139 mol) was added. The solution wasrefluxed for 24 hours. After cooling the solvent was evaporated undervacuum and the residue was chromatographed over silica gel(dichloromethane-methanol 9:1) to afford 4.5 g (21%) of the titlecompound, m.p. 187°-189° C. NMR (CDCl₃): delta_(H) =4.17 and 3.53 (ABq,J=16 Hz, 2H, NCH₂ CO), 1.5 (s, 3H, CH₃). MS (E.I., 70 eV, 1.5 mA)m/z=154 (M⁺), 139 (M-CH₃)⁺, 111 (M-CONH)⁺.

EXAMPLE 3(3S)-3,7a-Dimethyl-2,5-dioxohexahydro-1H-pyrrolo[1,2-a]imidazole

L-Alaninamide hydrochloride (20.7 g, 0.166 mol) and ethyl4-oxopentanoate (20 g, 0.13 mol) were reacted together according to theprocedure of Example 2 to give the title compound, 4.5 g (19.1%), m.p.228°-230° (with decomposition), [alpha]_(D) =+50.7° (c=3, H₂ O). NMR(CDCl₃): delta_(H) =7.95 (bs, 1H, NH); 4.30 (q, J=8 Hz, 1H, CHCH₃);3.00-2.10 (c.a., 4H, CH₂ CH₂); 1.60 (s, 3H, C-CH₃ ; 1.45 (d, J=8 Hz, 3H,CH₃ CH). MS (E.I., 70 eV, 1.5 mA) m/z=168 (M⁺), 153 (M-CH₃)⁺, 125(M-CHNO)⁺, 112 (M-C₃ H₄ O)⁺.

EXAMPLE 4 (3R,S)-3,7a-Dimethyl-2,5-dioxohexahydro-1H-pyrrolo[1,2-a]imidazole

DL-Alaninamide hydrochloride (6.9 g), 0.055 mol) and ethyl4-oxopentanoate (6.7 g, 0.043 mol) were reacted together according tothe procedure of Example 2 to give the title compound, 1.65 g (22.8%),m.p. 184°-192°. NMR (DMSO-d₆ : delta_(H) =8.80 (bs, 1H, NH); 3.90 (q,J=7.5 Hz, 1H, CHCH₃) 3.00-2.00 (c.a., 4H, CH₂ CH₂); 1.42 (s, 3H,C--CH₃); 1.22 (d, J=7.5 Hz, 1H, CHCH₃)

EXAMPLE 5 A) Isobutyl (4S)-4-methyl-5-oxo-2-imidazolidinepropanoate

To a suspension of L-alaninamide hydrochloride (2.4 g, 19.3 mmol) inbutanol (20 ml) isobutyl 4-oxobutanoate (3 g, 18.96 mmol) and sodiumcarbonate (1 g, 9.4 mmol) were added and the mixture was refluxed for 7hours. After cooling the precipitate was filtered off and the filtratewas evaporated to dryness. The residue was chromatographed over silicagel (dichloromethane-methanol 9:1) to afford 0.87 g (20%) of the titlecompound. Hydrochloride salt: m.p. 146°-148° C. (with decomposition).NMR (DMSO-d₆): delta_(H) =9.20 (bs, 1H, CONH); 4.80 (t, J=6 Hz, 1H,HN--CH--NH); 4.00 (q, J=8 Hz, 1H, CHCH₃); 3.83 (d, J=6 Hz, 2H, COOCH₂);3.40 (bs, 1H, CHNHCH); 2.90-2.65 (c.a., 2H, CH₂ CO); 2.25-1.75 (c.a.,3H, CH.sub. 2 CH₂ CO and CH(CH₃)₂); 1.37 (d, J=6 Hz, 3H, CH₃ CHNH); 0.87(d, J=6 Hz, 6H, CH(CH₃)₂). MS (E.I., 70 eV, 1.5 mA) m/z=228 (M⁺), 171(M-C₄ H₉)⁺, 155 (M-C₄ H₉ O)⁺, 99 (M-C₇ H₁₃ O₂)⁺.

B) (3S)-2,5-Dioxo-3-methylhexahydro-1H-pyrrolo[1,2a]imidazole

Isobutyl (4S)-4-methyl-5-oxo-2-imidazolidinepropanoate (0.870 g, 3.8mmol) was stirred without solvent at 110°-120° C. (external temperature)for 5 hours. The residue was chromatographed over silica gel(dichloromethanemethanol 9:1). The collected fractions were evaporatedand the residue was triturated with diethyl ether, to afford 0.4 q(68.2%) of the title compound, m.p. 126°-129° C. NMR (CDCl₃): delta_(H)=8.02 (bs, 1H, CONH); 5.35 (t, J=5 Hz, 1H, NCHNH); 4.30 (q, J=8 Hz, 1H,NCHCH₃); 2.90-1.80 (c.a., 4H, COCH₂ CH₂); 1.38 (d, J=8 Hz, 3H, CH₃ CH).MS (E.I., 70 eV, 1.5 mA) m/z=154 (M⁺), 139 (M-CH₃)⁺, 111 (M-CHNO)⁺, 98(M-C₃ H₄ O)⁺.

EXAMPLE 6 (3R,S)-2,5-Dioxo-3-methylhexahydro-1H-pyrrolo[1,2-a]imidazole

DL-Alaninamide hydrochloride (6.9 g, 0.055 mol) and isobutyl4-oxobutanoate (7.3 g, 0.046 mol) were reacted together according theprocedure of Example 2 to give the title compound, 1.7 g (24%), m.p.84°-86°. NMR (DMSO-d₆): delta_(H) =8.55 (bs, 1H, NH); 5.20 (t, J=5 Hz,NCHNH); 3.92 (q, J=6.5 Hz, 1H, CHCH₃); 2.82-1.50 (c.a., 4H, CH₂ CH₂);1.17 (d, J=6.5 Hz, 3H, CHCH₃). MS (E.I., 70 eV, 1.5 mA) m/z=154 (M⁺),111 (M-CHNO)⁺, 98 (M-C₃ H₄ O)⁺.

EXAMPLE 7 A) Isobutyl (4S)-4-isobutyl-5-oxo-2-imidazolidinepropanoate

L-Leucinamide hydrochloride (3.2 g, 19.2 mmol) and isobutyl4-oxobutanoate (3 g, 18.96 mmol) were reacted together according to theprocedure of example 5A to give the title compound, 1.7 g (33%).

Hydrochloride salt: m.p. 187°-188° C. (with decomposition). NMR(DMSO-d₆) delta_(H) =9.23 and 9.18 (bs, 1H, CONH); 4.92 and 4.85 (t, J=6Hz, 1H, NHCHNH); 4.10-3.80 (c.a., 1H, COCHNH); 3.82 (d, J=6 Hz, 2H,COOCH₂); 2.70-2.40 (c.a., 2H, CH₂ CO); 2.20-1.55 (c.a., 6H, CHCH₂CH(CH₃)₂, NHCHCH₂ CH₂ and COOCH₂ CH(CH₃)₂); 0.92 and 0.87 (d, J=6 Hz,12H, CH(CH₃)₂). MS (E.I., 70 eV, 1.5 mA) m/z=270 (M⁺), 213 (M-C₄ H₉)⁺,141 (M-C₇ H₁₃ O₂)⁺.

B) (3S)-2,5-Dioxo-3-isobutylhexahydro-1H-pyrrolo[1,2-a]imidazole

Isobutyl (4S)-4-isobutyl-5-oxo-2-imidazolidine propanoate (1.4 g, 5.4mmol) was heated at 130°-140° C. (external temperature) for 5 hours.Chromatography of the residue over silica gel (dichloromethane-methanol9:1) gave the title compound, 0.45 g (45%) m.p. 156°-157° C. NMR(CDCl₃): delta_(H) =7.35 (bs, 1H, CONH); 5.30 (t, J=6 Hz, 1H, NCHNH);4.22 (c.a., 1H, NCHCO); 2.75-1.40 (c.a., 7H, CH₂ CH₂ and CHCH₂ CH); 1.03and 0.90 (d, J=6 Hz, 6H, CH₃). MS (E.I., 70 eV, 1.5 mA) m/z=196 (M⁺),140 (M-C₃ H₄ O)⁺, 84 (M-C₆ H₁₀ NO)⁺.

EXAMPLE 8 2,5-Dioxo-1-ethylhexahydro-1H-pyrrolo[1,2-a]imidazole

Glycine ethylamide hydrochloride (2.1 g, 15.1 mmol) and isobutyl4-oxobutanoate (2 g, 12.6 mmol) were reacted together according theprocedure of Example 2 to give the title compound, 0.5 g (23.5%) as aviscous oil. Rf=0.51 (silica gel plates, eluent dichloromethane-methanol9:1). NMR (CDCl₃): delta_(H) =5.27 (t, J=6 Hz, 1H, N--CH--N); 4.20 and3.45 (ABq, J=17 Hz, 2H, N--CH₂ --CO); 3.25 (q, J=7 Hz, 2H, NCH₂ CH₃);2.70-1.75 (c.a., 4H, COCH₂ CH₂ CH); 1.12 (t, J=7 Hz, 3H, CH₃). MS (E.I.,70 eV, 1.5 mA) m/z=168 (M⁺), 112 (M-C₃ H₄ O)⁺, 97 (M-C₄ H₇ O)⁺.

EXAMPLE 9 2,5-Dioxohexahydro-1H-pyrrolo[1,2-a]imidazole

Glycinamide hydrochloride (4.2 g, 38 mmol) and isobutyl 4-oxobutanoate(5 g, 31.6 mmol) were reacted together according to the procedure ofexample 2, to give the title compound 1 g (22.6%), m.p. 154°-157° C.

EXAMPLE 10 Ethyl 2,5-dioxohexadro-1H-pyrrolo[1,2-a]imidazole-1-acetate

A mixture of 2,5-dioxohexahydropyrrolo-1H-[1,2-a]imidazole (0.5 g, 3.57mmol), tetrabutylammonium bromide (0.57 g, 1,78 mmol) and potassiumcarbonate (2.5 g, 17.8 mmol) in dry acetonitrile (6 ml) was stirred atroom temperature for 1 hour. Ethyl bromoacetate (0.5 ml, 4.53 mmol) wasadded and the suspension was heated at 60° C. for 2.5 hours. Theprecipitate was filtered off, the filtrate was evaporated under vacuumand the residue was chromatographed over silica gel (ethylacetate-acetonemethanol 6:3:1) to afford 0.7 g (92%) of the titlecompound, m.p. 75°-80° C. NMR (CDCl₃): delta_(H) =5.40 (c.a., 1H,N--CH--N); 4.21 (q, J=7.2 Hz, 2H, COOCH₂ CH₃); 4.32 e 3.68 (ABq, J=15.9Hz, 2H, NCH₂ CO); 4.30 and 3.80 (ABq, J=17.8 Hz, 2H, --CH₂ COOEt);2.80-1.70 (c.a., 4H, CH₂ CH₂) 1.28 (t, J=7.2 Hz, 3H, COOCH₂ CH₃). MS(E.I., 70 eV, 1.5 mA) m/z=226 (M⁺), 153 (M-CO₂ Et)⁺ ; 140 (M-CH₂ CO₂Et)⁺.

EXAMPLE 11 2,5-Dioxohexahydro-1H-pyrrolo[1,2-a]imidazole-1-acetamide

A solution of ethyl 2,5-dioxohexahydropyrrolo[1,2-a]imidazole-1-acetate(1.4 g, 6.18 mmol), in methanol (25 ml) was saturated with ammonia at 0°C. After stirring at room temperature for 16 hours the precipitate wascollected, washed with methanol and dried to yield 0.9 g (75%) of thetitle compound, m.p. 182°-185° C. NMR (DMSO-d₆): delta_(H) =7.50 and7.10 (2s, 2H, CONH₂); 5.25 (c.a. 1H, N--CH--N); 3.94 and 3.55 (ABq, J=16Hz, 2H, N--CH₂ CO); 3.85 and 3.70 (ABq, J=16.5 Hz, 2H, N--CH₂ CONH₂);2.90 and 1.90 (c.a., 4H, CH₂ CH₂). MS (E.I., 70 eV, 1.5 mA) m/z=139(M-CH₂ CONH₂)⁺.

EXAMPLE 12 A) Isobutyl (4S)-4-benzyl-5-oxo-2-imidazolidinepropanoate

To a solution of L-phenylalaninamide hydrochloride (20 g, 0.1 mol) inwater (200 ml), adjusted to pH 8.2 with 10% sodium hydroxide (about 35ml), was added isobutyl 4-oxobutanoate (16 g, 0.1 mol). The solution wasrefluxed for 24 hours. After cooling, the solution was extracted withdichloromethane (4×200 ml). The organic phase was dried and evaporatedto dryness under vacuum. The residue was chromatographed over silica gel(dichloromethanemethanol 9:1) to afford 6 g (20%) of the title compound,as an oil, which was characterized as the hydrochloride, m.p. 152°-155°C. (with decomposition) (after crystallization from ethanol-diethylether). NMR (DMSO-d₆, CDCl₃): delta_(H) =9.25 (b.s., 1H, CONH); 7.6-7.1(c.a., 5H, PhH), 4.90 (t, J=6.1 Hz, 1H, NHCHNH); 4.17 (t, J=6.1 Hz, 1H,CHCH₂ Ph); 3.84 (d, J=6.9 Hz, 2H, COOCH₂ CH); 3.35 (c.a., 2H, CH₂ Ph);2.50-1.60 (c.a., 5H, CH₂ CH₂ COO, CH₂ CH(CH₃)₂. MS (E.I., 70 eV, 1.5 mA)m/z=304 (M⁺), 213 M-C₇ H₇)⁺, 84 (C₃ H₄ N₂ O)⁺.

B) (3S)-3-Benzyl-2,5-dioxohexahydro-1H-pyrrolo[1,2-a]imidazole

A solution of isobutyl (4S)-4-benzyl-5-oxo-2-imidazolidinepropanoate(2.3 g, 7.33 mmol) in toluene (100 ml) was refluxed for 8 days. Afterevaporation of the solvent, the residue was chromatographed over silicagel (dichlorometane-methanol 9:1). The appropriate fractions werecollected and evaporated; the residue was triturated with diethyl etherto afford 850 mg (50%) of the title compound, m.p. 141°-145° C. NMR(CDCl₃): delta_(H) =7.25 (s, 5H, PhH); 7.02 (b.s., 1H, NH); 4.52 (t,J=4.5 Hz, 1H, PhCH₂ CH); 4.37 (t, J=5 Hz, 1H, NCHNH); 3.13 (d, J=4.5 Hz,2H, PhCH₂); 2.80-1.6 (c.a., 4H, CH₂ CH₂). MS (E.I., 70 eV, 1.5 mA)m/Z=230 (M⁺), 139 (M-C₇ H₇)⁺, 91 (C₇ H₇)⁺, 84 (C₄ H₆ NO)⁺.

EXAMPLE 13(3S)-3-Hydroxymethyl-2,5-dioxohexahydro-1H-pyrrolo[1,2-a]imidazole

L-Serine hydrochloride (10 g, 0.071 mol) and isobutyl 4-oxo-butanoate(11.25 g, 0.071 mol) were reacted together according to the procedure ofExample 2 to afford, after chromatography over silica gel(dichloromethane-methanol 8:2), 2.3 g (19%) of the title compound, m.p.150°-162° C. NMR (DMSO-d₆): delta_(H) =8.57 b s., 1H, NH); 5.15 (t, J=5Hz, 1H, N--CH--NH); 4.97 (ABCX System, 1H, CH₂ OH); 3.88-3.81 (ABCXSystem, 1H, CHCH₂ OH); 3.87-3.40 (ABCX System, 2H, CH₂ OH); 2.85-1.52(c.a., 4H, CH₂ --CH₂). MS (E.I., 70 eV, 1.5 mA) m/z=140 (M-CH₂ O)⁺, 84(C₃ H₄ N₂ O)⁺ and, as a by-product, 0.25 g of isobutyl (4S)-4-hydroxymethyl-5-oxo-2-imidazolidinepropanoate, m.p. 61°-75° C. NMR(DMSO-d₆): delta_(H) =8.1 (b.s., 1H, CONH); (c.a., 2H, NHCHNH, CH); 3.75(d, J=6.1, 2H, COOCH₂ CH); 3.55-2.90 (c.a., 4H, NH, CH--CH₂ --OH);2.50-2.30 (c.a., 2H, CH₂ COO); 2.00-1.40 (c.a., 3H, CH(CH₃)₂, CH₂ CH₂COO); 0.84 (d, J=6.1 Hz, 6H, CH(CH₃)₂). MS (E.I., 70 eV, 1.5 mA) m/z=213(M-CH₂ OH)⁺, 115 (C₆ H₁₁ O₂)⁺, 85 (C₃ H₅ N₂ O)⁺.

EXAMPLE 14 A) 2-Carboxy-4-oxo-2-imidazolidinepropanoic acid

A solution of 2-oxoglutaric acid (10 g, 0.068 mol), glycinamidehydrochloride (8.3 g, 0.075 mol) and sodium hydroxide (8.2 g, 0.205 mol)in water (120 mol) was refluxed for 4 hours. After cooling the solutionwas adjusted to pH 2.5 and the resulting precipitate was collected anddried under vacuum at 60° C. to afford 5.9 g (43%) of the titlecompound, m.p. 202°-205° C. NMR (DMSO-d₆): delta_(H) =8.5 (s, 1H, CONH);7.00-4.00 (b.s., 3H, NH, COOH); 3.22 and 3.18 (ABq, J=16 Hz, 2H, NHCH₂CO); 2.40-1.75 (c.a., 4H, CH₂ CH₂ COOH). MS (E.I., 70 eV, 1.5 mA)m/z=140 (M-H₂ O-COOH)⁺, 84 (C₃ H₄ N₂ O)⁺.

B) 2,5-Dioxohexahydro-1H-pyrrolo[1,2-a]imidazole-7a-carboxylic acid

A mixture of 2-carboxy-4-oxo-2-imidazolidinepropanoic acid (2 g, 9.89mmol), hexamethyldisilazane (20 mol) and trimethylchlorosilane (10 ml)in dry acetonitrile (50 ml) was refluxed under nitrogen for 4 hours.After cooling, the precipitate was filtered off and the filtrate wasevaporated under vacuum. The residue was dissolved in methanol (20 ml)containing some drops of concentrated hydrochloric acid and stirred for10 minutes. The insoluble material was filtered off and the filtrate wasevaporated to dryness. The residue was triturated with acetonitrile andcrystallized with tetrahydrofuran (250 ml) to yield 0.9 g (50%) of thetitle compound, m.p. 207° C. (with decomposition). NMR (DMSO-d₆):delta_(H) : 9.20 (b.s., 1H, NH); 3.82 and 3.46 (ABq, J=16.8 Hz, 2H, NCH₂CO); 2.90-1.80 (c.a., 4H, CH₂ --CH₂). MS (E.I., 70 eV, 1.5 mA) m/z=184(M⁺ ), 139 (M-COOH)⁺, 83 (C₃ H₃ N₂ O)⁺.

EXAMPLE 15 Ethyl2,5-dioxohexahydro-1H-pyrrolo[1,2-a]imidazole-7a-carboxylate

A solution of2,5-dioxohexahydropyrrolo-1H-[1,2-a]-imidazole-7a-carboxylic acid (0.8g, 4.34 mmol) in dry tetrahydrofuran (100 ml), was cooled to 0° C.,treated with oxalyl chloride (0.56 g, 4.34 mmol) and a drop ofdimethylformamide and stirred for 2 hours at 0° C. The solution wasstirred under vacuum at room temperature for 10 minutes. After coolingto 0° C., 4-dimethylaminopyridine (0.53 g, 4.34 mmol) and dry ethanol (2ml) were added. The suspension was stirred at 0° C. for 30 minutes andat room temperature for 30 minutes. The precipitate was filtered off andthe filtrate was evaporated under vacuum. The residue waschromatographed over silica gel (ethyl acetate-methanol 95:5) to afford0.45 g (49%) of the title compound, m.p. 116° C. NMR (DMSO-d₆):delta_(H) =9.22 (b.s., 1H, NH); 4.16 (q, J=7.4 Hz, 2H, COOCH₂ CH₃); 3.85and 3.48 (ABq, J=14.8, 2H, NCH₂ CO); 2.95-2.05 (c.a., 4H, CH₂ CH₂); 1.2(t, J=7.4 Hz, 3H, COOCH₂ CH₃). MS (E.I., 70 eV, 1.5 mA) m/z=183 (M-C₂H₅)⁺, 139 (M-COOC₂ H₅)⁺, 83 (C₃ H₃ N₂ O)⁺.

EXAMPLE 16 2,5-Dioxohexahydro-1H-pyrrolo[1,2-a]imidazole-7a-carboxamide

An ice cold solution of ethyl 2,5-dioxo-1H-hexahydropyrrolo[1,2-a]imidazole-7a-carboxylate (2,55 g, 12 mmol) in dry methanol (20ml) was treated with a saturated solution of ammonia in methanol (40 ml)and stirred for 1 hour at 0° C. The precipitate was collected, washedwith acetone and dried to afford 1.7 g (77%) of the title compound m.p.295° C. (with decomposition). NMR (DMSO-d₆): delta_(H) =9.05 (b.s., 1H,NH); 7.50 (b.s., 2H, CONH₂); 3.80 and 3.50 (ABq, J=14.8 Hz, 2H, NCH₂CO); 2.85-1.95 (c.a., 4H, CH₂ CH₂). MS (E.I., 70 eV, 1.5 mA) m/z=139(M-CONH₂)⁺, 83 (C₃ H₃ N₂ O)⁺.

EXAMPLE 17 2,5-Dioxo-1H-octahydroimidazo[1,2-a]pyridine

Glycinamide hydrochloride (4.24 g, 38.4 mmol) and methyl 5-oxopentanoate(5 ml, 38.4 mmol) were reacted together according to the procedure ofexample 2, to give 1.8 g (30%) of the title compound, m.p. 170°-174° C.NMR NMR (DMSO-d₆):delta_(H) =8.65. (b.s., 1H, CONH); 5.10-4.85 (c.a.,1H, NCHNH); 3.90 and 3.55 (ABq, J=14.8 Hz, 2H, N--CH₂ --CO); 2.40-1.10(c.a., 6H, (CH₂ CH₂ CH₂). MS (E.I., 70 eV, 1.5 mA) m/z=153 (M-H)⁺, 111(M-CONH)⁺, 84 (C₃ H₄ N₂ O)⁺.

EXAMPLE 18 A) Methyl 4-oxo-2-imidazolidinepentanoate

Glycinamide hydrochloride (6.73 g, 0.061 mol) and methyl 6-oxohexanoate(8.8 ml, 0.061 mol) were reacted together according to the procedure ofexample 2, to give 0.93 (7.6%) of the title compound, m.p. 58°-60° C.(with decomposition). NMR (DMSO-d₆): delta_(H) =8.10 (b.s., 1H, CONH);4.50-4.15 (c.a., 1H, NHCHNH); 3.55 (s, 3H, COOCH₃); 3.20 (b.s., 1H, CH₂NHCH); 3.05 (s, 2H, NHCH₂ CO); 2.45-2.10 (c.a., 2H, CH₂ COO); 1.80-1.10(c.a., 6H, CH₂ CH₂ CH₂ CH₂ COO). MS (E.I., 70 eV, 1.5 mA) m/z=200 (M⁺),169 (M-OCH₃)⁺, 85 (C₃ H₅ N₂ O)⁺.

B) 2,5-Dioxo-1H-octahydroimidazo[1,2-a]azepine

A solution of methyl 4-oxo-2-imidazolidinepentanoate (1 g, 5 mmol) intoluene (300 ml) was refluxed for 80 hours. After cooling the solutionwas evaporated and the residue was chromatographed over silica gel(dichlorometane-methanol 9:1) to afford 0.2 g (23%) of the titlecompound, m.p. 175°-176° C. NMR (DMSO-d₆) delta_(H) =8.60 (b.s., 1H,CONH); 5.35-5.10 (c.a., 1H, NCHNH); 3.70 (s, 2H, NCH₂ CO); 2.60-2.10(c.a., 2H, CH₂ CH₂ CON); 2.10-1.10 (c.a., 6H, CH₂ CH₂ CH₂). MS (E.I., 70eV, 1.5 mA) m/z=168 (M⁺), 85 (C₃ H₅ N₂ O)⁺.

EXAMPLE 19 A) Isobutyl 3-benzyl-5-oxo-2-imidazolidinepropanoatehydrochloride

A solution of N-benzylglycinamide (3.7 g, 0.022 mol) and isobutyl4-oxobutanoate (4 g, 0.023 mol) in dioxane (40 mol) and water (10 ml)was heated at 100° C. for 10 hours. After cooling, the solvent wasremoved under vacuum and the residue was treated with 10% hydrochloricacid (6 ml) to give a precipitate which was collected and trituratedwith acetone to afford 3.6 g (47%) of the title compound, m.p. 177° C.(with decomposition). NMR (DMSO-d₆): delta_(H) =9.2 (b.s., 1H, NH);7.80-7.30 (c.a, 5H, PhH); 4.90 (t, J=5 Hz, 1H, N--CH--NH); 4.50 and 4.30(ABq, J=13.6 Hz, 2H, CH₂ Ph); 3.80 (d, J=6.1 Hz, 2H, COOCH₂ CH); 3.68(s, 2H, CONH₂ N); 2.65-2.35 (c.a., 2H, CH₂ CH₂ COO); 2.20-1.50 (c.a.,3H, CH(CH₃)₂ and CH₂ CH₂ COO); 0.88 (d, J=6.1 Hz, 6H, CH(CH₃)₂). MS(E.I., 70 eV, 1.5 mA) m/z=304 (M⁺), 175 (M-C₇ H₁₃ O₂)⁺, 91 (C₇ H₇)⁺.

B) Isobutyl 5-oxo-2-imidazolidinepropanoate hydrochloride

To a mixture of 10% palladium on charcoal (1 g) and 99% formic acid (1ml) in methanol (25 ml), under nitrogen, was added a solution ofisobutyl 3-benzyl-5-oxo-2-imidazolidinepropanoate hydrochloride (1 g,2.93 mmol) and 99% formic acid (1.25 ml) in methanol (25 ml). Themixture was stirred under nitrogen for 6 hours. After addition of water(15 ml) and removal of the catalyst, the solvent was evaporated and theresidue was triturated with ethanol to give 0.3 g (41%) of the titlecompound, m.p. 136°-140° C. The same compound was obtained also by thefollowing procedure: into a mixture of isobutyl3-benzyl-5-oxo-2-imidazolidinepropanoate hydrochloride (2.2 g, 6.4mmol), and 10% palladium on charcoal (1.1 g) in water-methanol 2:1 (150ml) hydrogen was bubbled at room temperature and at atmospheric pressurefor 2 hours. Removal of the catalyst and evaporation of the solventunder reduced pressure gave a residue which was triturated with ethanolto afford 1.4 g (90%) of the title compound, m.p.136°-140° C. NMR(DMSO-d₆): delta_(H) =11.1-9.50 (b.s., 2H, NH₂ ⁺); 9.20 (b.s., 1H,CONH); 4.95 (t, J=6.2 Hz, 1H, NHCHNH); 3.84 (d, J=6.7 Hz, 2H, COOCH₂);3.65 (s, 2H, NCH₂ CO); 2.70-2.30 (c.a., 2H, CH₂ CH₂ COO); 2.25-1.60(c.a., 3H, CH₂ CH₂ COO, CH(CH₃)₂); 0.87 (d, J=6.7 Hz, 6H, CH(CH₃)₂. MS(E.I., 70 eV, 1.5 mA) m/z=214 (M⁺), 141 (M-OC₄ H₉)⁺, 85 (C₃ H₅ N₂ O)⁺.

C) 2,5-Dioxohexahydro-1H-pyrrolo[1,2-a]imidazole

A solution of isobutyl 5-oxo-2-imidazolidinepropanoate hydrochloride(1.4 g, 5.76 mmol) in water (100 ml) was treated with sodium hydrogencarbonate (0.54 g, 6.4 mmol) and heated at 100° C. for 20 hours. Thesolution was evaporated and the residue was chromatographed over silicagel (ethyl acetate-acetone-methanol 6:3:1) to afford 300 mg (37%) of thetitle compound, m.p. 155°-157° C.

EXAMPLE 20 A) Ethyl 1-benzyl-4-oxo-2-imidazolidinepropanoate

A suspension of N-benzylglycinamide (35.5 g, 0.22 mol) and ethyl4-oxobutanoate (31 g, 0.24 mol) in toluene (370 ml) was refluxed for 6hours in a Dean-Stark apparatus. After cooling, the mixture wasextracted twice with 10% sulphuric acid (200+100 ml); the aqueousextracts were neutralized with sodium hydrogen carbonate and extractedtwice with toluene (250 ml each time). The organic solution was washedwith water (100 ml), dried (MgSO₄) and evaporated under vacuum to affordan oil which was triturated with a mixture of diethyl ether-lightpetroleum (1:2) to give 45 g (75%), of the title compound as a yellowsolid, m.p. 60°-62° C. NMR (CDCl₃): delta_(H) =7.5 (bs, 1H, NH); 7.30(bs, 5H, PhH); 4.5-4.25 (ABX, 1H, CH-M); 4.13 (q, J=6.9 Hz, 2H, OCH₂);4.00 and 3.53 (ABq, J=12.4 Hz, 2H, PhCH₂); 3.37 and 3.02 (ABX, J=14.9Hz, 2H, NCH₂ CO); 2.65-2.30 (c.a., 2H, CH₂ CH₂ CO); 2.20-1.15 (c.a., 2H,CH₂ CH₂ CO); 1.24 (t, J=6.9 Hz, 3H, CH₃). MS (E.I., 70 eV, 1.5 mA)m/z=276 (M⁺), 231 (M-OEt)⁺, 185 (M-PhCH₂)⁺, 175 (M-C₅ H₉ O₂)⁺, 91(PhCH₂)⁺.

B) 2,5-Dioxohexahydro-1H-pyrrolo[1,2-a]imidazole

To a suspension of 10% palladium on charcoal (11.6 g) in water (60 ml),a solution of ethyl 3-benzyl-5-oxo-2-imidazolidinepropanoate (58 g, 0.21mol) and ammonium formate (52.9 g, 0.84 mol) in methanol (580 ml) wereadded. The mixture was refluxed under nitrogen for 1 hour. After coolingto 40° C., 32% ammonia (145 ml) was added and the temperature wasmaintained between 40° and 50° C. for 1.5 hours. After cooling to roomtemperature, the catalyst was removed by filtration and the solution wasevaporated to dryness. The residue was diluted with water (700 ml) andstirred in the presence of ion exchange resins Amberlite IR 120 H (200ml) and Amberlite IRA 68 (200 ml) for 1.5 hours. The resins werefiltered off and washed with water (600 ml). The clear solution wasevaporated under vacuum at 60° C. to afford an oil which was dried byazeotropic distillation with ethanol. The resulting residue wastriturated with acetone (75 ml) to afford 19.7 g (67%) of the titlecompound as a white solid, m.p. 154°-157° C.

What is claimed is:
 1. A compound of structure (1) ##STR5## wherein R¹is hydrogen, C₁₋₄ alkyl, CHR⁶ CONHR⁷ l or CHR⁶ COOR⁷ in which R⁶ and R⁷are each hydrogen or C₁₋₄ alkyl;R² is hydrogen, C₁₋₅ alkyl, C₆ H₅ CH₂,CH₂ OH, CH₂ CH₂ CONH₂ or CH₂ COOH; R³ is hydrogen, C₁₋₄ alkyl, CONH₂ orCO₂ R⁸ in which R⁸ is hydrogen, or C₁₋₄ alkyl, and n is 4;or apharmaceutically acceptable salt thereof.
 2. A compound of structure (1)as claimed in claim 1 in which R¹ to R³ are each hydrogen.
 3. Thecompound according to claim 1 wherein R² is hydrogen, or C₁₋₅ alkyl. 4.The compound according to claim 3 wherein R² is --CH₃, or --CH(CH₃)₂. 5.A compound of structure (1) as claimed in claim 1 whichis:2,5-dioxo-1H-octahydroimidazo[1,2-a]azepine.
 6. A pharmaceuticalcomposition comprising a compound of structure (1) or a pharmaceuticallyacceptable salt thereof as claimed in claim 1 and a pharmaceuticallyacceptable carrier.
 7. A pharmaceutical composition according to claim 6wherein the compound of structure (1) is2,5-dioxo-1H-octahydroimidazo[1,2-a]azepine.
 8. A method of restoringlearning and treating memory difficulties which comprises administeringto a subject in need thereof a non-toxic effective amount of a compoundof structure (1) as described in claim 1.